Certain 2-substituted-5,8-dihydro-5-oxopyrido{8 2,3-d{9 pyrimidine-6-carboxylic acid derivatives

ABSTRACT

WHEREIN R1 stands for hydrogen or a lower alkyl radical; R2 stands for hydrogen, a lower alkyl radical, hydroxyl group, a halogen atom, a lower alkoxy radical, an amino radical or a lower alkylthio radical; R3 stands for hydrogen, a lower alkyl radical, hydroxyl group, a lower alkoxy radical, a lower alkylthio radical or a radical represented by the formula (WHEREIN R&#39;&#39; stands for hydrogen, an alkyl radical, a cycloalkyl radical, an amino radical, a hydroxyalkyl group or an alkyl substituted amino alkyl radical, and R&#39;&#39;&#39;&#39; stands for hydrogen or an alkyl radical, R&#39;&#39; and R&#39;&#39;&#39;&#39; may be the same or a different radical and R&#39;&#39; and R&#39;&#39;&#39;&#39; may bond together to form a 5- or 6membered heterocyclic ring containing a nitrogen hetero atom); and R4 stands for hydrogen or an alkyl group. Such derivatives are useful as antibacterial agents. A 5,8-dihydro-5-oxopyrido (2,3-d) pyrimidine derivative represented by the following formula

il'nited States atent Minami et al.

[ June 27, 1972 [54] CERTAIN 2-SUBSTITUTED-5,8-

DiHYDRO-5-0XOKYRIDO[2,3- D]PYRlMIDINE-6-CARBOXYLIC ACID DERIVATIVES [72] Inventors: Shinsaku Minami, Kouriyama; Toshihlro Shono, Takatsuki; Masanao Shmmizu, Kobe; Yoshlyuki Takase, Amagasaki, all of 260/2564 C, 260/2564 N, 260/2565 R, 260/482 P, 260/484 P, 260/534 E, 260/535 P, 424/25l [51] Int. Cl. ..C07d 57/20 [58] Field of Search ..260/256.4 F, 256.5 R, 247.2 R, 260/2472 B [56] References Cited UNITED STATES PATENTS 3,322,765 5/1967 Hitchings et al. ..260/256.4

OTHER PUBLICATIONS Mulvey et al., Chem. Abstracts, 61 :I 3306c I964) Primary Examiner-Alex Mazel Assistant Examiner-R. J. Gallagher Attorney-Sherman and Shalloway [57] ABSTRACT A 5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine derivative represented by the following formula wherein R stands for hydrogen or a lower alkyl radical; R stands for hydrogen, a lower alkyl radical, hydroxyl group, a halogen atom, a lower alkoxy radical, an amino radical or a lower alkylthio radical; R stands for hydrogen, a lower alkyl radical, hydroxyl group, a lower alkoxy radical, a lower alkylthio radical or a radical represented by the formula (wherein R stands for hydrogen, an alkyl radical, a cycloalkyl radical, an amino radical, a hydroxyalkyl group or an alkyl substituted amino alkyl radical, and R" stands for hydrogen or an alkyl radical, R and R may be the same or a different radical and R and R" may bond together to form a 5- or 6- membered heteroeyclic ring containing a nitrogen hetero atom); and R stands for hydrogen or an alkyl group. Such derivatives are useful as antibacterial agents.

10 Claims, N0 Drawings It can be expected that the compound will be useful in treatment of bacterial infections in man and animals. Also, the compound will be useful in the fields of foods and agriculture.

The novel compound of this invention of a 5,8-dihydro-- oxopyrido [2,3-d] pyrimidine derivative is a compound represented by the following formula (IV wherein R stands for hydrogen or a lower alkyl radical, R stands for hydrogen, a lower alkyl radical, hydroxyl group, a halogen atom, a lower alkoxy radical, an amino group or a lower alkylthio radical, R stands for hydrogen, a lower alkyl radical, hydroxyl group, a lower alkoxy radical, a lower alkylthio group or a radical represented by the formula (wherein R' stands for hydrogen, an alkyl radical, acycloalkyl radical, an amino radical a hydroxyalkyl radical or an alkylsubstituted aminoalkyl radical, R" stands for hydrogen or an alkyl radical, R and R" may be the same or different, and R" and R" may bond together to form a heterocyclic ring), and R stands for hydrogen or an alkyl radical.

A lower alkyl radical referred to herein directs to a straight chain or branched chain alkyl radical having 1-6 carbon atoms, while a lower alkoxy radical and a lower alkylthio radical referred to herein directs to an alkoxy radical and an alkylthio radical each having l-6 carbon atoms corresponding to said lower alkyl radical.

Further, the compound of said formula (IV) sometimes forms an organic amine salt at the position of R and the formula (IV) of this invention is defined as including such salts.

Of R hydrogen, a lower alkyl radical, hydroxyl group and a halogen atom are preferable groups as compared with other R 's, and as an alkyl radical of R,, a lower alkyl radical is preferable.

Heretofore, in the compound of this invention of said formula (IV), the following compound having different substituents at 5.-position and 6-position, but having the same ring structure has been known as an antibacterial agent. Typical examples of these known compounds are the compound of the following fonnula described in Belgian Pat. No. 658,069, namely (wherein R stands for an alkyl having l-4 carbon atoms, R, stands for hydrogen or an alkyl oraralkyl having l-4 carbon atoms, and R and R may bond to form a divalent alkylene bridge), the compound of the following formula described in Belgian Pat. No. 657,922, namely I |lH2 (wherein R stands for an alkoxy or an alkyl having l-4 carbon atoms), and the compound of the following formula described in British Pat. No. 970,583, namely (wherein R stands for an alkyl, a phenalkyl or an alkyl-substituted phenyl).

The ring structure common to these known compounds are formed by similar means. For instance, when an explanation is made of the compound of said Belgian Pat. No. 657,992 as an example, such compounds are prepared by halogenating 3- tert. amino-acrolein of the following formula, namely likBN CHO (wherein ABN is a tert. amino and R is an alkyl or alkoxy having l-4 carbon atoms), and heating the halogenated 3-tert. amino-acrolein with 2,4,6-triaminopyrimidine.-

The objective compound of this invention represented by said formula (IV) and the compound of following formula (III) which is an intermediate thereof of which mention will be made later in connection with an explanation about the process for the preparation are both novel compounds. The compound of formula (W) is more excellent in that it shows a high anti-microorganism activity against many pathogenic microorganisms and the preparation thereof is easy.

Further, though the ring structure is different from that of the compound of this invention, in Belgian Pat. No. 612,258, a compound A of the following formula is described as an antibacterial agent having a high activity.

Ali-Ht g It is true that this compound is one of the excellent anti-bacterial agents; however it has lower in vitro antibacterial activity and more toxicity than the preferable compound of this invention. For instance, 6-carboxy5,8-dihydro-2- dimethylamino-8-ethyl-5-oxopyrido [2,3-d] pyrimidine [compound (B)] and 6-carboxy-5,8-dihydro-8-ethyl-2-methylthio- 5-oxopyrido [2,3-d] pyrimidine, both belonging to the compound of this invention, show excellent antibacterial activities against a broad range of pathogenic microorganisms as will be shown later in Table III, and MIC of said compound (B) is 10 TABLEI 5 Acute toxicity in mice (survived/tested) dose i.p. p.o.

compound(A)' lg/kg /5 3/5 compound (B) lg/kg 4/5 5/5 Observation was made on 7th day after administration.

Accordingly, an object of this invention is to provide novel compounds having an excellent antibacterial activity.

Another object of this invention is to provide processes for the preparation of such compounds.

Further objects and advantages of this invention will become clearer from the following description.

Of the novel compound of this invention represented by the formula (IV), from the viewpoint of a broad scope of application and excellent medicinal effect, (i). a novel 5,8-dihydro-5- oxopyrido [2,3-d] pyrimidine of which R, is hydrogen and R is an alkyl radical in the formula (IV) and (ii). a novel 5,8- dihydro-S-oxopyrido [2,3-d] pyrimidine of which R and R are hydrogen or a lower alkyl group and R is a lower alkylthio radical or [wherein R and R" are as defined in the formula (IV)] in the formula (IV) are two examples showing preferable compounds. In the latter case of (ii) when R, is hydrogen and R is an alkyl radical, it becomes an embodiment wherein the case of(i) is further limited in respect of R Next, an explanation will be made about a process for the preparation of the novel compound having an antibacterial activity of this invention.

The novel compounds of this invention can be easily prepared by ring-closing upon heating intermediates of formula (III) to be mentioned later, which are novel compounds. An N-(6-pyrimidinyl) aminomethylene malonic acid derivative of formula (III) can be prepared by two methods, and when they are mentioned together, they are as follows.

lh Rt) 7 (Method [1) C\ N I 000R. R -X on 3 I 11111 (1) B4 (II) R? 000R, R2 0 l l l w 5 coon I h 000R, h u l 6 H 2 1 R- R 1 s (III) (IV) (wherein R R R and R are as defined in the formula (IV), R stands for a lower alkyl and X stands for a halogen atom).

Namely, in order to obtain the novel compound (IV) of this invention, one may be obtained by the reaction of an aminopyrimidine derivative represented by formula (I) with an alkoxymethylene malonic acid derivative represented by formula (II) (Method a), or the reaction of a halogenopyrimidine derivative represented by formula (I) with an aminomethylene molonic derivative represented by formula (11') (Method b) to form the novel intennediate of formula (III) and heating to ring-close said compound of formula (IV).

The reaction of method a may be carried out as follows. The object of Method a can be achieved by heating the compound of formula (I) and the compound of formula (II) per se or in an inert solvent such as alcohols or dioxane. The reaction temperature is 80l50 C., preferably l00-l 30 C.

The reaction of Method b may be carried out as follows. The compound of formula (I') and thecompound of formula II) are heated in a sealed tube. This reaction may also be carried out in-the absence of a solvent; however, preferably it is better to carry out the reaction in an inert solvent such as alcohols or dioxane. As the reaction temperature, a temperature within the range of from 80 to C. is preferably selected.

The obtained N-(G-pyrimidinyl) aminomethylene malonic acid derivative of formula (III) is a novel compound, which can be converted into a 5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine of formula (IV) easily by heating which brings about a ring closure reaction.

The ring closure reaction of the intermediate of formula (III) to the compound of formula '(IV) may be carried out in the absence of a solvent; however, preferably it is carried out in the presence of an inert organic solvent such as ethylene glycol monoalkyl ether, diphenylether and a mineral oil under heating conditions. As said inert organic solvent, those having a boiling point in the vicinity of the reaction temperature are preferable. It is better to carry out the reaction using such a solvent under refluxing conditions. As the reaction temperature, a broad range of from a considerably low temperature to a high temperature can be adopted; however, normally a temperature of l00-300 0, preferably a temperature in the vicinity of 250 C. is adopted.

The obtained reaction product may be purified by recrystallization according to the conventional method using, as occasion demands, a proper solvent such as, for instance,

methanol, ethanol, chloroform, butanol and acetone.

When in the obtained novel compound shown by formula (IV), 5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine derivative, R at 8-position is hydrogen, it is deemed that the novel compound exists as a ketoenol type tautomere concerned with the oxygen at 5-position. It should be understood that fonnula (IV) includes such a case.

Further, in this invention it is possible to convert a compound shown by said formula (IV) to another compound shown by the same formula. Hereinbelow, the main modes of practice will be explained.

1. Of the objective compound (IV) of this invention, a compound whose R, is hydrogen, viz. 6-position is occupied by a free carboxylic acid may be easily obtained by hydrolyzing a compound whose R is a lower alkyl, viz. 6-position is occupied by an ester with an alkali saponifier or an acid saponifier.

As such known saponifiers, a caustic alkali or an alkali carbonate such as sodium hydroxide, potassium hydroxide and sodium carbonate and mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid may be cited. When an alkali saponifier is used, caustic alkalis are preferable to alkali carbonates in the capacity of hydrolysis.

As a hydrolysis reaction, it is sufficient to heat said compound with these alkalis or acids for a short period. Adaption of an excessively high temperature and/or an excessively long heating period is undesirable because of the tendency to bring about a side reaction. Generally, heating at a temperature below 100 C. for several minutes will do.

Upon converting a compound of which R is a lower alkyl in formula (IV) to another compound of which R is hydrogen by this hydrolysis, when R, is a lower alkyl and R is a lower alkoxy radical, a lower alkylthio radical or a radical represented by the formula [wherein R and R" are as defined in the formula (IV)], the substituent at 2-position, viz. R is hydrolyzed simultaneously with R and converted to a hydroxyl group.

Also, it is possible to hydrolyze a compound whose R is hydrogen atom, namely 6-position is occupied by a free carboxylic acid, whose R, is a lower alkyl radical, and whose R, is a lower alkoxy radical, a lower alkylthio radical or a radical represented by the formula (wherein R, stands for a hydroxyl group when R, stands for a lower alkoxy, a lower alkylthio or (wherein R and R are as mentioned above), and R, is an alkyl radical, otherwise R is same as R while R,, R R and R, are as defined above.)

2. Of the objective compound (IV) of this invention, an compound whose R, is an alkyl, namely, 8-position is substituted by an alkyl may be easily obtained from a compound whose R, is hydrogen by utilizing a known alkylation.

This reaction of converting a compound of the formula (IV) to another compound of the same formula (IV) but utilizing alkylation can be shown by the following formula.

(wherein R R R and R, are as defined in the formula (IV) and R, stands for a lower alkyl). v

This alkylation may be carried out by using a known alkylating agent, for instance, an alkyl halide, a dialkyl sulfate and an alkyl sulfonate. The reaction may'be carried out by merely containing said compound whose R, is hydrogen with these alkylating agents. When, for instance, a dialkyl sulfate or an alkyl'sulfonate is used, thereaction proceeds merely by stirring. When an alkyl halide is used, normally it is better to carry out the reaction by heating.

Normally, it is better to carry out the reaction in water or an organic solvent inert to the reaction system such as, for instance, water, dimethylformamide and aliphatic alcohols in which a compound whose R, is hydrogen may be able to dissolve or suspend. As mentioned above, the reaction may be carried out at room temperature or under heating conditions. Normally, as the heating temperature about C. is suitable.

This conversion of a compound whose R, is hydrogen to a compound whose R, is an alkyl may be more accelerated by adding an alkali substance such as, for instance, potassium carbonate to the reaction system. When a compound whose R, is hydrogen and whose R is a lower alkyl compound is alkylated by the use of a strong alkali such as, for instance, a

caustic alkali like sodium hydroxide or potassium hydroxide as an alkali substance, sometimes R is simultaneously hydrolyzed and said compound is converted to another com.- pound whose R is hydrogen, viz. 6-position is occupied by a free carboxylic acid.

3. Further, of the objective compound (IV) of this invention, an amino substituent whose R is [wherein R and R are as defined in the formula (IV)] can be obtained by reaction of amines of the formula RI HN (wherein R and R" are as mentioned above) with a compound of the formula (IV) whose R is a lower alkoxy radical or a lower alkylthio radical.

When this reaction of converting a compound of the formula (IV) to another compound of the same formula (IV) by utilizing said amination is shown by formulas, it can be shown asfollows.

R, 0 R2 0 I II I ll 000R, I COOR, I l l l amination s N N N N N RI! 1k: R;

(wherein R,, R,, R and R" are as defined in the formula (IV), R stands for a lower alkoxy radical or a lower alkylthio radical, and R stands for an alkyl radical).

This amination is normally carried out in a solvent. As such [wherein R,, R and R are as defined in the fonnula (IV)].

This reaction may be carried out in a proper inert solvent such as alcohols and dioxane at a temperature of 50200 C.

solvent,ansolvent inert to the reaction system under the reac- 5 in the presence of a metal catalyst such as Raney nickel. tion conditions such as, for instance, water, aliphatic alcohols, benzene, toluene, xylene, halogenoalkanes, tetrahydrofuran Th in the pr of this invention, as mentioned above and dioxane may be cited. The reaction proceeds at room the j f nfwel o p of a ,8-di yd -5- py i o temperature also; however, preferably it is better to carry out [2 d] pyrimidine erivative is Obtaine by ring-Closing upon the reaction at a temperature of 50-150 C. under the heating h ing h n l omp f h formula of an conditions. Moreover, the reaction may be carried out under pyrimidinyl) aminomethylene malonic acid derivative formed atmosphere or pressure; however, it is better to carry out the by reaction of the compound of the formula (I) with the comreaction under a pressure, for instance 2-10 atmospheres. pound of the formula (II) or reaction of the compound of the 4. Of the objective compound (IV) of this invention, a comformula (I') with the compound of the formula (II'). Further, pound whose R is hydrogen is obtainable from another comif desired as mentioned in the aforesaid (l)-(4), it is possible pound of the formula (IV) whose R is a lower alkylthio by to obtain the objective product by converting a compound of desulfurization. the formula (IV) to another compound represented by the This reaction of converting a compound of the formula (IV) same formula (IV). to another compound of the same formula (IV) by utilizing desulfurization can be shown by the following formulas. 2O

Accordmgly, the process of this invention contains N processes for preparing the compound of the formula (III), a 1/ process for preparing the compound of the formula (IV) and @COORI processes for converting the compound of the formula (IV) to desuuuflzaflo 2 5 another compound represented by the compound of the same k N 4 n formula (IV) and obtaining the ob ective compound by I properly combining these processes. 4 R2 0 Next, a few examples of the novel compound of this inven- N 00011 tion of a 5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine deriva- I tive will be shown in Table II below. However, the compound H-k of (l)-(6), (51), (52) and (54) are illustrations of the interf mediate which will become the objective compounds by ring- 7 7 It; closing upon heating.

TABLE 11 No. Compound Structure M .1. C.

1. Etfiggglglggi i-dimethyl-G-pyrimidinyl)aminomethylene (3H3 /C O 0 02115 I 102-103 L C O 0 c 2H CH3 v N NE 2. Et gfiofigihydroxyt-pyrimidinyl)aminomethylene- C O O CLHS 191-494 p L I oooczH I-IO 3. Ethyl N-(4-methyl-6-pyrimidiny1)aminomethylene- CH3 101. 5-102 malonate. C O O CZHs N L l J C 0 0 C 2H5 N N H 4 Ethyl N-(4-hydroxy-2-methy1thio-fi-pyrimidinyl)amino- OH 228230 methylenemalonate. 1 C O O C2115 {1 f0 0 0 0211 CH s a N N H Ethyl N-(4-chIoro-2-1n ethylthio-(i-pyrimidinyl)aminomethylenomalonato.

COOC Hs TABLE II-Continued I No. Compound Structure Ml. C.

45... 6-carb0xy-5,B-dihydro 2-dirnethylamino-8-isopropyl-fi- 0 251-253 oxopyr1do[2,3-d]pyrimidine. 1]

C OOH CH3 N i N N cm OH: I

41; 4i-uurlmxy-5,H-dihydro-H-ethyl-2-l1ytlruzino-5-oxopyrido[2,3-d] 250-261 pyrimidine. I

lium'lmxyofi-rlilIylli'o-iZ-dorlucylmnino-8-cLhyl-5-0xopyrldo O i 160-163 l2,3-d]pyrimiilino (lodvcylmnim salt. ll

' mooon-clmcmmmh CII3(CII2)uNH N N I CzHs 48..." G-carboxy-S,8-dihydro-B-ethyl-2pctadecylamino-5-oxopyrido O 160-163 [2,3-d]pyrimidine octadecyclamincsalt. l

N COOH-GHACHQMNH CQHS 4l. G-carboxy-S,8-dihydro-4-liydroxy-Z-methylthio-S-oxopyrido OH 0 287-9 [2,3-dlnyrimidine.

N 1 COOH CHaS-Lm N 50 (i-carboxy-5,8-dil1ydro-2-dimethylamin0-5-oxopyrid0[2,3-d] O 4 300 305 pyrimidine.

OOOH cm N v i A CH II 51". Ethyl N-(Q-nmthylthioA-pyrimidinyl) mninomi-vthylune- COOCZII 106-7 nmloimtv. N

k i I COOCJL, CHaS \NAN/ 52. EthylN-(24ml.hoxy-4pyrimidinyl)mninonmthylone- 00001115 123-125 malmmtu. N

i COOC2H 53 6-carhoxy-5,8F lil1ydro-Q-methoxy-S-oxopyrid0[2,3d] 0 pyrimidine.

N coon CHaO \N/ H 54- Ethyl N-(Z-GimethylaminoA-pyrimidinyD-N-ethyl umino- COOCHE 148-150 methylenemalonate. N

& L I 0000211 N N N C a i The novel compound of this invention of a 5,8-dihydro-5- oxopyrido[2,3-dlpyrimidine derivative has an antibacterial bercle bacilli, being useful as a medicine and useful as an intermediate for the preparation of another compound having activity against Gram positive, Gram negative bacteria and tu- 75 antibacterial activity.

isms. The minimum inhibitory concentration (MIC) was determined by well known serial dilution technique.

- EXAMPLE 4 (Example of synthesis of the compound of formula (III) according to method a) 4-Amino2-hydroxypyrimidine (1.4 g) and 3.0 g of ethyl TABLE IIL-ANTIBACTERIAL ACTIVITY IN VITRO Compound No.

6) (2 (3 Organism Staphylococcus aureus 30 10 30 30 30 30 30 10 30 30 30 30 1 Escherichia coli 3 1 3 10 10 3 10 1 10 10 I .10 10 30 Shigzlla flezuorl 2a. 3 3 10 30 30 1O 30 10 10 3O 10 10 30 Shzgella sonneL 1 1 3 10 10 3 10 3 10 10 10 10 3O Salmonella typhimuri 3 1 3 1O 3O 10 10 3 10 10 10 3 10 Proteus vulgaris 3 1 3 10 10 3 10 l 3 10 10 10 10 K lrbsiella pueumrmiaa 1 0.3 1 3 3 1 3 1 1 3 3 3 3 Salmonella mlcritidis 1 1 3 10 10 3 10 3 30 v 10 3 10 30 M ycnlnrctcrium tuberculosis 30 10 30 10 30 10 30 30 30 10 30 30 The table IV summarizes in vivo activities of the compound against infection with Salmonella typhimurium in mice.

TABLE IV'.THERAPEUTIC EFFECT IN MICE (SURVIVED/ TESTED) [Organismz Salmonella typhimurium; Route of infection: i .p.; Route of administration: p.o.]

Compound No.

ltouton p.o. p.0. p.o. 11.0.

[)oso:

100 mix/k 6/10 8/10 6/10 6/10 5Il11lg./kg 4/10 7/10 2/10 5/10 rug/kg... 1/10 5/10 4/10 12.5 rug/kg 3/10 1 2 times per day for 4 days.

- N o'ru .S urvival rate of non-treated control was 0/10.

The 5,8-dihydro-5 0xopyrido[2,3-d]pyrimidine (deriva tive) of this invention may be used in external, oral and injectable forms or in combination .with other drags. Accordingly, this invention contains antibacterial agents having the compound of the formula (IV) as an effective component. Next, explanations will be made about a few modes of practice of this invention by examples.

EXAMPLE 1 (Example of synthesis of the compound of formula (III) according to method a) 6-Amino-2,4-dimethylpyrimidine 12.2 g.) and 23.0 g of ethyl ethoxymethylene malonate were heated, while stirring, for 35 minutes at a temperature of 110 to 120 C. The resulting product was cooled and recrystallized from ethanol. There was obtained 18.5 g of ethyl N-(2,4-dimethyl-6-pyrimidinyl) aminomethylene malonate having a melting point of 102 to 103 C.

EXAMPLE 2 (Example of synthesis of the compound of formula (III) according to method a) 4-Amino-2-methylthiopyrimidine (29.0 g) and 60.0 g of ethylethoxymethylene malonate were heated, while stirring, for 1 hour and 40 minutes at a temperature of 135 to 140 C. The resulting product was cooled and recrystallized from ethanol. There was obtained 33.7 g of ethyl N-(Z-methylthio- -pyrimidinyl) aminomethylene malonate having a melting point of 106 to 107 C.

EXAMPLE 3 ethoxymethylene malonate were subject to reaction for 20 minutes at to C. After cooling the reaction product, the obtained crystals were recrystallized from ethanol. There was obtained 2.4 g of ethyl N-(2-hydroxy-4-pyrimidinyl) amino methylene malonate having a melting point of 191-19 4 C.

The following compounds were obtained .by the same method as above mentioned.

1. Ethyl N-(4-methyl-6-pyrimidinyl) aminomethylene malonate having a melting point of 10l.5102 C. from 6- amino-4-methylpyrimidine and ethyl ethoxymethylene malonate.

2. Ethyl N-(4-hydroxy-2-methylthio-6-pyrimidinyl) aminomethylene malonate having a melting point of 228-230 C. from 6-amino-4-hydroxy-2-methylthio pyrimidine and ethyl ethoxymethylene malonate.

3. Ethyl N-(4-chloro-2-methylthio-6 pyrimidinyl) aminomethylene malonate having a melting point of 132-134 C. from 6-amino-4-chloro-2-methylthio-pyrimidine and ethyl ethoxymethylenemalonate.

Ethy1-N-(2-dimethylamino-4-pyrimidinyl1 aminomethylene malonate having a melting point of 5963 C. from 4-amino-2-dimethylaminopyrimidine and ethyl ethoxymethylene malonate.

EXAMPLE 5 N-(2-dimethylamino-4-pyrimidinyl)-N-ethyl aminomethylene malonate. The picrate of this compound has a melting point of EXAMPLE 6 (Example of synthesis of the compound of formula (III) according to method b) 4-Chloro-2-dimethylamino pyrimidine (200 mg) and 300 mg of ethyl aminomethylene malonate were added to 30 ml of ethanol, and the mixture was reacted for 6 hours at 140 C. in a sealed tube. At the end of the reaction, the solvent was removed by distillation under reduced pressure. The resulting product was recrystallized from ethanol to give 280 mg of ethyl N-(2-dimethylam ino-4-pyrimidinyl) aminomethylene malonate having a melting point of 59-63 C.

The following compounds were obtained in the same manner as above mentioned.

1. Ethyl N-(2-methylthio-4-pyrimidinyl) aminomethylene malonate having a melting point of 106-107 C. from 4- chloro-2-methylthiopyrimidine and ethyl aminomethylene malonate.

2. Ethyl N'-(2-methoxy-4-pyrimidinyl) aminomethylene malonate having a melting point of l23-l25 C. from 4- chloro-2-methoxypyrimidine and ethyl aminomethylene malonate.

EXAMPLE 7 (Example of synthesis of the compound of formula (IV) from the compound of formula (III) Ethyl N-(2-methylthio-6-pyrimidinyl) aminomethylene malonate obtained in Example 2 (43.0 g) was added to 270 ml of boiling diphenyl ether, and the mixture was heated under reflux for 25 minutes. After cooling, 400 ml of n-hexane was added to the product. The precipitated crystals were recovered by filtration and washed with ethanol to give 26.4 g of 5,8-dihydro-6-ethoxycarbonyl-2-methylthio-5-oxopyrido [2,3-d] pyrimidine having a melting point of 26927 1 C.

EXAMPLE 9 (Example of synthesis of the compound of formula (IV) from the compound formula (III) Ethyl N-(2-methoxy-6-pyrimidinyl) aminomethylene malonate obtainedin Example 3 (1.16 g) was added to 15 ml of boiling diphenyl ether, and the mixture was vigorously heated under reflux for 10 minutes. After cooling, 50 ml of nhexane was added to the product. The precipitated crystals were recovered by filtration and recrystallized from ethanol to give 0.64 g of 5,8-dihydro-6-ethoxycarbonyl-2-methoxy-S-oxopyrido [2,3-d] pyrimidine having a melting point of 23523 7 C.

EXAMPLE 10 (Example of synthesis of the compound of formula (IV) from the compound of formula (III) Ethyl N-( 2-hydroxy-4-pyrimidinyl) aminomethylene malonate (610 mg) was added to ml of boiling diphenyl ether, and the mixture was heated for minutes under reflux. After cooling, 10 ml of n-hexane was added to the product. The precipitated crystals were recovered by filtration, and recrystallized from methanol to give 330 mg of 5,8-dihydro-6- ethoxycarbonyl-2-hydroxy-5-oxopyrido [2,3-d] pyrimidine having a melting point of 25826l C.

EXAMPLE 1 1 (Example of synthesis of the compound of formula (IV) from the compound of fonnula (III) Ethyl N-(4-hydroxy-2-methylthio-6-pyrimidinyl) aminomethylene malonate (2.10 mg) was added to 3 ml of diphenyl ether, and the mixture was refluxed for 13 minutes. To the product was added 15 ml of n -hexane. The precipitated crystals were recovered by filtration and recrystallized from ethanol-chloroform to give mg of 5,8-dihydro-6-eth0xycarbonyl-4-hydroxy-2-methylthio-S-oxopyrido [2,3-d] pyrimidine having a melting point of 26l263 C.

EXAMPLE 12 (Example of synthesis of the compound of formula (IV) from the compound offormula (III) Ethyl N-(2-dimethylamino-4-pyrimidinyl) aminomethylene malonate (10 g) was added to 50 ml of diphenyl ether under reflux, and the mixture was reacted for 20 minutes. After cooling, 200 ml of n-hexane was added to the product. The precipitated crystals were recovered by filtration, and washed with ethanol to give 8.0 g of 5,8-dihydro-2-dimethylamino-6- ethoxycarbonyl-S-oxopyrido [2,3-d] pyrimidine having a melting point of 290-295 C.

EXAMPLE 1 3 (Example of conversion of the compound of fonnula (IV) by alkylation into another compound of formula (IV) A mixture of 2.9 g of 5,8-dihydro-2,4-dimethyl-6-ethoxycarbonyl-S-oxopyrido [2,3-d] pyrimidine, 25 g of dimethylformamide, 10 g of ethyl iodide and 10 ml of a 20percent aqueous solution of potassium carbonate was stirred for 1 hour at C. The precipitated potassium iodide was separated by filtration, and dimethylformamide was removed by distillation under reduced pressure. A saturated aqueous sodium chloride was added to the resulting product, and it was extracted with chloroform, followed by recrystallization from ethanol. There was obtained 1.95 g of 5,8-dihydro-2,4- dimethyl-6-ethoxycarbonyl-8-ethyl-5-oxopyrido.

pyrimidine having a melting point of 156.5 l 58 C.

EXAMPLE 14 (Example of conversion of the compound of formula (IV) by alkylation into another compound of formula (IV) A mixture of 0.32 g of 5,8-dihydro-6-ethoxycarbonyl-2- methylthio-S-oxopyrido [2,3-d] pyrimidine, 2.6g of dimethylformamide, 1.l g of ethyl iodide and 2 ml of a 20 percent aqueous solution of potassium carbonate was treated in the same manner as in Example 13 to give 0.30 g of 5,8-dihydro-6- ethoxycarbonyl-8-ethyl-2-methylthio-5-oxopyrido [2,3-d] pyrimidine having a melting point of l44.5-l45 C.

EXAMPLE 15 (Example of conversion by alkylation) A mixture of 100 mg of 5,8-dihydro-6-ethoxycarbonyl-2- methoxy-S-oxopyrido [2,3-d] pyrimidine, 1.0 g of dimethylformamide, 300 ml of ethyl iodide and 1 ml of a 20 percent aqueous solution of potassium carbonate was treated in the same manner as in Example 13. The reaction product was recrystallized from acetone-n-hexane to give 82 mg of 5,8 dihydro-6-ethoxycarbonyl-8-ethyl-2-methoxy-5-oxopyrido [2,3-d] pyrimidine having a melting point of l47-l49 C.

EXAMPLE 16 (Example of conversion by alkylation) 6-Carboxy-5,8-dihydro-2-methylthio-5-oxopyrido [2,3-d] pyrimidine (7.0 g) was dissolved in a 4 percent aqueous solution of potassium hydroxide, and on addition of 5.0 g of diethyl sulphate, the solution was vigorously stirred at room temperature for 2 hours. After having been left to stand overnight, the reaction product was acidified with acetic acid. The precipitated crystals were recovered by filtration, washed with water, and recrystallized from methanol to give 7.2 g of 6-carboxy-5,8-dihydro-8-ethyl-2-methylthio-5-oxopyrido [2,3-d] pyrimidine having a melting point of 25 3256 C.

EXAMPLE l7 (Example of conversion by alkylation) 6-Carboxy-5 ,8-dihydro-2-methoxy-5-oxopyrido {2,3-d]

pyrimidine (100 mg) was dissolved in 5 ml of a 4 percent aqueous solution of potassium hydroxide, and on addition of diethyl sulphate, the solution was treated in the same manner as in Example 16. The resulting product was recrystallized from chloroform-acetone to give 98 mg of 6-carboxy 5,8- dihydro-8-ethyl-2-methoxy-S-oxopyrido [2,3-d] pyrimidine having a maleing point of 254-256 C.

EXAMPLE 18 (Example of conversion by alkylation) EXAMPLE 19' (Example of conversion of alkylation) 5,8-Dihydro-6-ethoxycarbonyl-2-methylthio-5-oxopyrido [2,3d] pyrimidine (200 mg) was suspended in ml of ethanol-water.( 1:1) containing 0.4 g of potassium hydroxide, and on addition of 500 mg of diethyl sulphate, the suspension was stirred for 4 hours while cooling. After having been left to stand overnight, the product was acidified with acetic acid. The precipitated crystals were. recovered by filtration, and recrystallized from chloroform to give 108 mg of 6-carboxy- 5,8-dihydro-8-ethyl-2-methylthio-5-oxopyrido- [2,3-d]

pyrimidine having a melting point of 253255 C.

EXAMPLE 20 (Example of conversion by alkylation) The following compounds were obtained in the same manner as in Example 19.

l. 6-Carboxy-5,8-dihydro-2-rnethylthio-5-oxo-8-n-propylpyrido [2,3-d] pyrimidine having a melting point of l97l99 C.

2. 8-N-butyl-6-carboxy-5,8-dihydro-2-methylthio-5-oxopyrido [2,3-d] pyrimidine having a melting point of 174l7 6 C.

3. 6'Carboxy-5,8-dihydro-8-isopropyl-2-methylthio-5-oxopyrido [2,3-d] pyrimidine having a melting point of 23l-233C.

EXAMPLE 21 (Example of conversion by hydrolysis) 5,8-Dihydro-6-ethoxycarbonyl 2-methylthio-5-oxopyrido [2,3-d] pyrimidine (20.0 g) was added to 200 ml of a 7 percent aqueous solution of sodium hydroxide, and the solution was heated for 20 minutes at 100 C. The product was acidified with acetic acid. The precipitated crystals were recovered by filtration and recrystallized from a great quantity of methanol to give 12.5 g of 6-carboxy-5.,8-dihydro-2- methylthio-S-oxopyrido [2,3-d] pyrimidine having a melting point of 27928 1 C.

EXAMPLE 22 (Example of conversion by hydrolysis) 5,8-Dihydro-6-ethoxycarbonyl-2-methoxy-5-oxopyrido [2,3-d] pyrimidine (400 mg) was added to 8 ml of a 5 percent aqueous solution of sodium hydroxide, and the solution was heated for minutes at 90 C. The resulting product was acidified with acetic acid. The precipitated crystal were recovered by filtration, and recrystallized from a great quantity of methanol-acetone to give 290 mg of 6-carboxy-5,8- dihydro-2-methoxy-5-oxopyrido [2,34] pyrimidine having a melting point of above 250 C.

EXAMPLE 23 (Example of conversion by hydrolysis) 5,8-Dihydro-2,4-dimethyl-6-ethoxycarbonyl-S-ethyl-S-oxopyrido [2,3-d] pyrimidine (1.2 g) was added to 15 ml ofa 10 percent aqueous solution of sodium hydroxide, and the solution was heated for 1 hour and 30 minutes at 125 C. The resulting product was acidified with acetic acid. The

precipitated crystals were recovered by filtration, and recrystallized from ethanol. to give 0.77 g of 6carboxy-5,8- dihydro-2,4-dirnethyl-8-ethyl-5-oxopyrido [2,3-d] pyrimidine having a melting point of 222-224 C.

EXAMPLE 24 (Example of conversion of hydrolysis) 5,8-Dihydro-2,4-dimethyl-6-ethoxycarbonyl-5-oxopyrido [2,3-d] pyrimidine 165 mg) was added to 8ml of a 10 percent aqueous solution of sodium hydroxide, and the solution was heated for 1 hour and 30 minutes at l20l30 C. The resulting product was acidified with acetic acid. The'precipitated crystals were recovered by filtration, and recrystallized from ethanol to give 109 mg of 6*carboxy-5,8-dihydro-2,4- dirnethyl-S-oxopyrido [2,3-d] pyrimidine having a melting point of 266-267 C. EXAMPLE 25 (Example of conversion by hydrolysis) 6-Carboxy-5,8-dihydro-8-ethyl-2-methylthio-5-oxopyrido [2,3-d] pyrimidine (47 mg) was added to 1 ml of a 5 percent caustic soda, and the mixture was heated for 15 minutes at -95 c. After cooling, the resulting product was acidified with acetic acid. The precipitated crystals were recovered by filtration and recrystallized from a great quantity of ethanol to give 31 mg of 6-carboxy-5,8-dihydro-8-ethyl-2-hydroxy-5-oxopyrido [2,3-d] pyrimidine having a melting point of 287-29 EXAMPLE26 (Example of conversion by hydrolysis) 5.8-Dihydro--ethoxycarbonyl-8-ethyl-2-methoxy-5-oxopyrido [2,3-d] pyrimidine (50 mg) was added to 1 ml of a 5 percent caustic soda, and the mixture was heated for 5 minutes at C. The subjection of the resulting product to the same treatment as in Example 25 gave 33 mg of 6-carboxy-5,8-dihydro8-ethyl-2-hydroxy-5-oxopyrido [2,3-d] pyrimidine.-

EXAlvlPLE 27 (Example of conversion. by hydrolysis) 5,8-Dihydro-6-ethoxycarbonyl-8-ethyl-2-methylthio-5-oxopyrido [2,3-d] pyrimidine (200 mg) was added to 4 ml of a 5 percent caustic soda, and the mixture was heated for 15 minutes at 90-95 C. The subjection of the resulting product to the same treatment as in Example 25 gave 123 mg of 6-carboxy-5,8-dihydro-8-ethyl-2-hydroxy-5-oxopyrido [2,3-d] pyrimidine.

EXAMPLE 28 (Example of conversion by hydrolysis) Five hundred milligrams of 5,8-dihydro-6-ethoxycarbonyb4 -hydroxy-2-methylthio-5-oxopyrido [2,3-d] pyrimidine was added to 10 ml of a 7 percent caustic soda, and the mixture was heated for 13 minutes at 90 C for hydrolysis. The product was acidified with acetic acid. The precipitated crystals were recovered by filtration, and recrystallized from methanolchloroform to give 370 mg of 6-carboxy-5,8-dihydro-4- hydroxy-2-methylthio-5-oxopyrido [2,3-d] pyrimidine having a melting point of 287289 C. V

EXAMPLE 29 (Example of conversion by hydrolysis) 5,8-Dihydro-2-dimethylamino-6-ethoxycarbonyl-5-ox opyrido [2,3-d] pyrimidine (7.0 g) was added to ml of a 7 percent caustic soda, and the mixture was heated for 30 minutes at C. for hydrolysis. The product was acidified with acetic acid. The precipitated crystals were recovered by filtration, and recrystallized from acetonitrile. There was ob tained 5.6 g of -carboxy-S,8-dihydro-2-dimethylamino-5-oxopyrido [2,3-d] pyrimidine having a melting point of 300-30 3 0.

EXAMPLE (Example of conversion of the compound of formula (IV) by amination into another compound of formula (IV) Seven hundred milligrams of 5,8-dihydro-6-ethoxycarbonyl-8-ethyl-2-methylthio-5oxopyrido [2,3-d] pyrimidine was added to 30 ml of absolute ethanol containing 2 g of dimethylamine, and the mixture was heated in a sealed tube for 6 hours at 95 C. The solvent was removed by distillation, and the residue was recrystallized from ethanol. There was obtained 560 mg of 5,8-dihydro-Z-dimethylamino-dethoxycarbonyl-8-ethyl-5-oxopyrido. [2,3-d] pyrimidine having a melting point of l63l64.5 C.

' EXAMPLE 31 (Example of conversion by amination) Seven hundred milligrams of 6-carboxy-5,8-dihydro-8- ethyI-Z-methylthio-S-oxopyrido [2,3-d] pyrimidine was treated in quite the same manner as in Example 30. There was obtained 530 mg of 6-carboxy-5,8 -dihydro-2-dimethylamin o- 8-ethyl-5-oxopyrido [2,3-d] pyrimidine having a melting point of 28829l C.v

EXAMPLE 32 (Example of conversion by amination) One hundred and fifty milligrams of 6-carboxy-5,8-dihydro- 8-ethyl-2-methylthio-5-oxopyrido [2,3-d] pyrimidine was added to 30 ml of absolute ethanol. Into this mixture was dissolved 2.0 g of methylarnine, and the solution was heated for 7 hours at 105 C. in a sealed tube. The solvent was removed by distillation, and the residue was washed with ethanol and recrystallized from methanol-chloroform. There was obtained 120 mg of 6-carboxy-5,8-dihydro-8'ethyl-2-methylamino-5- oxopyrido [2,3-d] pyrimidine having a melting point of 274-276 C.

When in this example the same treatment was carried out with the use of n-butylamine, n-hexylamine, isopropylamine, cyclohexylamine, ethanolarnine, diethylaminopropylarnine, dirnethylarninopropylarnine and ethylamine in place of methylamine, the following compounds were obtained.

1. 2-N-butylamino-6-carboxy-5,8-dihydro-8-ethyl-5-oxopyrido [2,3-d] pyrimidine (126 mg; m.p. l92-194 C.)

fi-Carboxy-5,8-dihydro-8-ethyl-2-n-hexylamino5-oxopyrido [2,3-d] pyrimidine (137 mg; m.p. l64l66 C.) 3. 6-Carboxy-5,B-dihydro-8-ethyl-2-isopropylamino-5-oxopyrido [2,3-d] pyrimidine (124 mg; m.p. 233235 C.) 4. 6-Carboxy-2-cyclohexylamino5,8-dihydro-8-ethyl-5-oxopyrido [2,3-d] pyrimidine (131 mg; m.p. 2092l 1 C.) 6-Carboxy-5,8-dihydro8-ethyl-2-( 2-hydroxyethyl)amino-5-oxopyrido [2,3-d] pyrimidine (118 mg; m.p. 268270 C.)

6-Carboxy-2-[3-(diethylamino) propylamino]-5,8- dihydro-B-ethyl-S-oxopyrido [2,3-d] pyrimidine 142 mg; m.p. l60l62 C.) 7. 6-Carb0xy-5,8-dihydro2-[3-( dirnethylamino) propylamino]-8-ethyl-5-oxopyrido [2,3-d] pyrimidine (135 mg; m.p. l65-l67 C.) 8. 6-Carboxy-5,8-dihydro8-ethyl-2-ethylamino-5-oxopyrido [2,3-d] pyrimidine (107 mg; m.p. 269272 C.)

EXAMPLE 33 (Example of conversion by amination) Two hundred milligrams of 6-carboxy5,8-dihydro-8-ethyl- 2-methylthio-5-oxopyrido [2,3-d] pyrimidine was added to 30 ml of absolute ethanol containing 1.2 g of ammonia, and the mixture was reacted for 5.5 hours at 105 C. in a sealed tube. The solvent was removed by distillation, and the residue was recrystallized from ethanol to give 127 mg of 2-amino-6-carboxy-5,S-dihydro-8-ethyl-5-oxopyrido [2,3-d] pyrimidine having a melting point of 29 l293 C.

EXAMPLE 34 (Example of conversion by amination) One hundred and fifty milligrams of 6-carboxy-5,8-dihydro- 8-ethyl-2-methylthio-5-oxopyrido [2,3-d] pyrimidine was added to 30 ml of absolute ethanol containing 1.1 g of piperidine had been dissolved, and the mixture was reacted for 5 hours at C. in a sealed tube. The solvent was removed by distillation, and the residue was recrystallized from methanolchloroform. There was obtained 112 mg of 6-carboxy-5,8- dihydro-8-ethyl-5-oxo-2-piperidino-pyrido [2,3-d] pyrimidine having a melting point of 267270 C. p

EXAMPLE 35 (Example of conversion by amination) I When morpholine was used instead of piperidine in Example 34, there was obtained 121 mg of 6-carboxy-5,8-dihydro'8 -ethyl-2-morpholino-5-oxopyrido [2,3-d] pyrimidine having a melting point of 270-272 C.

EXAMPLE 36 (Example of conversion by amination) When pyrrolidine was used instead of piperidine in Example 34, there was obtained 1 l 1 mg of 6-carboxy-5,8-dihydro-8- ethyl-S-oxo-Z-pyrrolidinopyrido [2,3-d] pyrimidine having a melting point of 3 143 16 C.

EXAMPLE 37 (Example of conversion by amination) Two hundred milligrams of 6carb0xy-5,8-dihydro-8- methyl-Z-methylthio-S-oxopyrido [2,3-d] pyrimidine was suspended in 30 ml of absolute ethanol containing 6 g of dimethylamine, and the suspension was reacted for 6 hours at 105 C. in a sealed tube. The product was heated and filtered. The solvent was removed by distillation from the filtrate, and the residue was recrystallized from chloroform-methanol. There was obtained 124 mg of 6-carboxy S,8-dihydro-2-' dimethylamino-8-methyl-5-oxopyrido [2,3-d] pyrimidine having a melting point of 3 l23 15 C.

EXAMPLE 38 (Example of conversion by amination) The following compounds were obtained in the same manner as in Example 37.

1. 8-N-butyl-6-carboxy-5,8-dihydro-2-dimethylamino-5-oxypyrido [2,3-d] pyrimidine having a melting point of 205-207 C.

2. 6-Carboxy-5,8-dihydro-2-dimethylamino-5-oxo-8-n-propylpyrido [2,3-d] pyrimidine having a melting point of 26l-262 C.

3. 6-Carboxy-5,8-dihydro-2-dimethylamino-8-isopropyl-5- oxo-pyrido [2,3-d] pyrimidine having a melting point of 251-253 C.

EXAMPLE 39 (Example of conversion by amination) Two hundred milligrams of 6-carboxy-5,8-dihydro-8-ethyl- 2-methyl-5-oxopyrido [2,3-d] pyrimidine and mg of hydrazine were added to 40 ml of ethanol, and the mixture was heated for 15 minutes under reflux. The precipitated crystals were recovered by filtration, and after washing with ethanol, they were suspended in water. Three to five drops of a 10 percent hydrochloric acid were added to the suspension, and the crystals were dissolved. The resulting solution was filtered. The filtrate was made alkaline with potassium carbonate, and then acidified with acetic acid. The precipitated crystals were recovered by filtration, and recrystallized from methanol. There was obtained 121 mg of 6-carboxy5,8-

having a melting point of 25926l C.

:7 EXAMPLE 4O dodecylamino-8-ethyl-5oxopyrido [2,3-d] pyrimidine having a melting point of 160l 63 C.

EXAMPLE 41 (Example of conversion by amination) Two hundred milligrams of 6-carboxy-5,8-dihydro-8-ethyl- Z-methylthio-S-oxopyrido [2,3-d] pyrimidine and 1.0 g of octadecylamine were added to 30 ml of ethanol, and the mixture was reacted for 6.5 hours at 105 C. in a sealed tube. The solvent was removed by distillation, and the residue was recrystallized fromvethanol to give 347 mg of an octadecylamine salt, of 6-carboxy-5,8-dihydro-8-ethyl-2-octadecylamino-S-oxopyrido [2,3-d] pyrimidine having a melting point of l60i-l63 C.

EXAMPLE 42 (Example of conversion by desulfu'rization) Seven hundred milligrams of 6-carboxy-5,8-dihydro-8- ethyl-Z-methylthio-S-oxopyrido [2,3-d] pyrimidine was dissolved in 30 ml of dioxane, and on addition of 4 g of Raney nickel (W-4), the solution was refluxed for 3 hours. At the end of the reaction, the Raney nickel was separated by filtration. The filtrate was distilled and the residue was recrystallized .from ethanol to give 420 mg of 6-carboxy-5,8-dihydro-8- ethyl-S-oxopyrido [2,3-d] pyrimidine having a melting point of 21 9-222 C.

What is claimed is:

l. A 5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine derivative represented by the following formula (IV) m4: 0 OR, Rz-k (wherein R stands for hydrogen, an alkyl radical with up to 18 carbon atoms, cyclohexyl, amino, hydroxyloweralkyl, loweralkylaminoloweralkylene, R" stands for hydrogen or lower alkyl, and NR R" may be morpholino, piperidino, or pyrrolidino); and R is hydrogen or a lower alkyl.

2. The 5,8-dihydro-S-oxopyrido.[2,3-d] pyrimidine derivative of claim 1 wherein R, is H; R, is H; R318 wherein R and R" are-as defined above; and R, is C H 3. The 5,8-dihydro-S-oxopyrido -[2,3-d] pyrimidine derivative of claim 1 wherein R, is H; R, is H; R, is a lower alkylthio radical; and R is'C,H

4. The 5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine derivative of claim lvwherein R, is H; R, is H; R, is a lower alkoxy radical; and R is C H 5. The 5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine derivative of claim 1 wherein R, is Q H R, is H; R, is

wherein R' and R" are as previously defined; and R is C H 6. The, 5,8-dihydro-5-oxopyrldo [2,3-d] pyrimidine d erivative of claim 1 wherein'R, is H; R is H; R is a lower alkylthio radical; and R, is H.

7. The 5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine derivative of claim 1 wherein the compound is 6.-carboxy-5,8- dihydro-2-dimethylamino-8-ethyl-S-oxopyrido [2,3-d] pyrimidine.

8.'The 5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine derivative of claim 1 wherein the compound is 6-carboxy-5,8- dihydro-8ethyl-2-morpholino-5oxopyrido [2,3-d] pyrimidine.

9. The 5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine derivative of claim 1 wherein the compound is 6-carboxy-5,8- dihydro-8-ethyl-5oxo-2-piperidino-pyrido [2,3-d] pyrimidine.

10. The 5,8-dihydro-5 -ox0pyrido [2,3-d] pyrimidine derivative of claim 1 wherein the compound is 6-carboxy-5,8- dihydro-8-ethyl-5-oxo-Z-pyrrolidino-pyrido [2,3-d] pyrimidine. 

2. The 5,8-dihydro-5-oxopyrido (2,3-d) pyrimidine derivative of claim 1 wherein R1 is H; R2 is H; R3 is wherein R'' and R'''' are as defined above; and R4 is C2H5.
 3. The 5,8-dihydro-5-oxopyrido (2,3-d) pyrimidine derivative of claim 1 wherein R1 is H; R2 is H; R3 is a lower alkylthio radical; and R4 is C2H5.
 4. The 5,8-dihydro-5-oxopyrido (2,3-d) pyrimidine derivative of claim 1 wherein R1 is H; R2 is H; R3 is a lower alkoxy radical; and R4 is C2H5.
 5. The 5,8-dihydro-5-oxopyrido (2,3-d) pyrimidine derivative of claim 1 wherein R1 is C2H5; R2 is H; R3 is wherein R'' and R'''' are as previously defined; and R4 is C2H5.
 6. The 5,8-dihydro-5-oxopyrido (2,3-d) pyrimidine derivative of claim 1 wherein R1 is H; R2 is H; R3 is a lower alkylthio radical; and R4 is H.
 7. The 5,8-dihydro-5-oxopyrido (2,3-d) pyrimidine derivative of claim 1 wherein the compound is 6-carboxy-5,8-dihydro-2-dimethylamino-8-ethyl-5-oxopyrido (2,3-d) pyrimidine.
 8. The 5,8-dihydro-5-oxopyrido (2,3-d) pyrimidine derivative of claim 1 wherein the compound is 6-carboxy-5,8-dihydro-8-ethyl-2-morpholino-5-oxopyrido (2,3-d) pyrimidine.
 9. The 5,8-dihydro-5-oxopyrido (2,3-d) pyrimidine derivative of claim 1 wherein the compound is 6-carboxy-5,8-dihydro-8-ethyl-5-oxo-2-piperidino-pyrido (2,3-d) pyrimidine.
 10. The 5,8-dihydro-5-oxopyrido (2,3-d) pyrimidine derivative of claim 1 wherein the compound is 6-carboxy-5,8-dihydro-8-ethyl-5-oxo-2-pyrrolidino-pyrido (2,3-d) pyrimidine. 